Acetyl CoA carboxylase (ACC) is an enzyme that carboxylates acetyl CoA to produce malonyl CoA, and mammals have two isozymes of ACC1 and ACC2 in their own bodies. Malonyl CoA produced by ACC may be a starting material for long-chain fatty acids or triglycerides, and in addition, it may negatively control carnitine palmitoyl transferase-1 (CPT-1) which participates in oxidative decomposition of fatty acids. Of the above isozymes, ACC1 exists in cytoplasm and is considered as a rate-limiting enzyme in biosynthesis of long-chain fatty acids; while ACC2 exists predominately in mitochondria and is said to participate principally in oxidation of fatty acids. Accordingly, compounds capable of inhibiting ACC1 and/or ACC2 are expected not only to inhibit synthesis of fatty acids but also to reduce accumulated fat. It is known that high cellular fat and fatty acids, as well as malonyl CoA which is generated by ACC2, induce insulin resistance in animals and play an important role in type 2 diabetes. In fact, it was shown that, as compared with normal mice which became obese and diabetic on a high fat/high carbohydrate diet, ACC2-knock out mice on a high fat/high carbohydrate diet had reduced obesity due to increased fatty acid oxidation and reduced fat storage, remained insulin sensitive, and did not develop diabetes. (see Proceedings of the National Academy of Sciences of the United States of America, 100 (18), pp. 10207-10212, 2003; Science, Vol. 291, pp 2613-2616 (2001)).
An excess of accumulated fat may cause, for example, insulin resistance, diabetes, hypertension, hyperlipemia and obesity, and it is known that a plurality of those factors, as combined, lead to a higher risk of arteriosclerosis and metabolic syndrome. Further, it is known that hypertriglyceridemia or obesity leads to a higher risk of, for example, pancreatitis, hepatic dysfunction, cancers such as breast cancer, uterine cancer, ovarian cancer, colon cancer and prostate cancer, emmeniopathy, arthritis, gout, cholecystitis, gastroesophageal reflux, Pickwickian syndrome, and sleep apnea syndrome. It is well known that diabetes often causes, for example, cardiac angina, heart failure, stroke, claudication, retinopathy, eyesight failure, renal failure, neuropathy, skin ulcer, infectious diseases (see The Merck Manual of Medical Information, second home edition, Merck & Co., 2003). Accordingly, ACC inhibitors are useful for the treatment and/or prevention of such disorders.
ACC exists also in plants, parasites, bacteria and fungi, and participates in the growth of cells. For example, aryloxyphenoxypropionic acid-type herbicides represented by diclofop, and cyclohexanedione-type herbicides represented by sethoxydim exert their activity by inhibiting ACC in plants (see Biochemical Society Transaction, 22(3), p. 616 (1994)), and aryloxyphenoxypropionic acid also exhibits a growth-inhibiting effect on parasites (see Journal of Biological Chemistry, 277 (26), pp. 23208-23215 (2002)). Soraphen and moiramide B, known ACC inhibitors, exhibit an antibacterial effect and an antifungal effect (see Current Genetics, 25 (2), pp. 95-100 (1994); Journal of Biological Chemistry, 279 (25), pp. 26066-26073 (2004)).
Tumor cells generally show an increased synthesis of fatty acids, and it is reported that some fatty acid synthesis inhibitors exhibit a cell growth-inhibiting effect.
Based on the above-mentioned information, ACC inhibitors are expected to be useful for the treatment and/or prevention of disorders such as hyperlipemia, dyslipidemia, hepatic steatosis, hepatic dysfunction, non-alcoholic fatty liver disease, obesity, diabetes, insulin resistance, metabolic syndrome, arteriosclerosis, hypertension, cardiac angina, heart failure, cardiac infarction, stroke, claudication, retinopathy, eyesight failure, renal failure, electrolyte abnormality, neuropathy, skin ulcer, bulimia, pancreatitis, emmeniopathy, arthritis, gout, cholecystitis, gastroesophageal reflux, Pickwickian syndrome, sleep apnea syndrome, infectious diseases, neoplasia, and also as herbicides.
There still remains a need for potent low molecular weight ACC1 and ACC2 inhibitors that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.
Up to the present, for example, those described in WO 2003/094912, WO 2003/072197, WO 2003/059886, and WO 2003/059871 are known as compounds capable of inhibiting ACC, but the compounds described in these references are structurally distinct from the compounds of the present invention.
On the other hand, various compounds having a spirochromanone skeleton are disclosed in U.S. Pat. Nos. 5,206,240, 5,633,247, JP2005119987A, EP 431973A, EP 004624 A2, WO 94/17045, WO 95/30642, WO 96/39140, and WO 2004/092179. However, these references neither disclose nor suggest the ACC-inhibiting effect of the compounds disclosed therein or of the compounds of the present invention.